Herpes simplex type-2 (HSV-2) is the primary cause of genital ulcers, and one of the most prevalent sexually transmitted diseases worldwide. Consistently, over 20 studies have found HSV-2 infection to be a risk factor for HIV acquisition with an overall relative risk of 2.1 in the more rigorous studies. A recent study of HIV-discordant couples from Rakai, Uganda, has shown that at all levels of HIV viral load in the HIV-positive partner, HSV-2 infection in the susceptible partner increased the per-contact risk of acquisition of HIV 5-fold. As strong as these epidemiologic data are, an intervention trial is required to define the clinical and public health significance of these findings. This proposal is to conduct a proof-of-concept, randomized, double-blind, placebo-controlled trial to assess the efficacy of HSV-2 suppression with daily acyclovir on HIV acquisition among two groups with high rates of HSV-2 prevalence and high risk of incident HIV: heterosexual women in Zambia and Zimbabwe and men who have sex with men (MSM) in the U.S. and Peru. The hypothesis is that standard doses of daily acyclovir 400mg bid will reduce HIV incidence by 50 percent in heterosexual women and MSM by decreasing rates of clinical and subclinical HSV-2 reactivation. The specific aims are: 1) To measure the efficacy of daily generic acyclovir 400 mg PO bid in preventing HIV acquisition among HSV-2 seropositive, HIV-negative heterosexual women and MSM at high risk for HIV infection; 2) To determine the effect of twice daily acyclovir suppressive therapy on reducing the frequency of genital ulcers and subclinical HSV-2 reactivation among HSV-2 seropositive, HIV-negative persons; and 3) To assess adherence with twice daily acyclovir suppressive therapy among HSV-2 seropositive, HIV-negative persons. A total of 1100 women and 1100 MSM will be enrolled at 5 sites and followed for a mean of 18 months for incident HIV infection. This intervention trial will directly answer the extent to which HSV-2 infection increases susceptibility to HIV infection, and the relative reduction in HIV incidence among HSV-2 seropositive persons treated with daily suppressive antiviral therapy. Acyclovir has an acceptable safety profile for widespread STD treatment and is inexpensive and well-tolerated. Given high rates of HSV-2 infection worldwide in persons at risk for HIV, this approach could have great public health importance by providing a safe, acceptable, and cost-effective method to reduce HIV susceptibility among high-risk HIV-negative heterosexuals and MSM.